This project will identify genetic factors that predict individual resilience to cognitive impairment arising from Alzheimer's disease (AD) or cerebrovascular disease. At autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD or cerebrovascular disease. Yet, to date very little research has focused on the genetic factors that might contribute to such resilience. The objective of this application is to identify genetic variants that modify the association between AD pathology, cerebrovascular disease, and cognitive impairment. This work will leverage data from 6 datasets across the country to both discover and replicate such gene-environment interaction effects. In addition, it will look for interactions using both in vivo biomarker data and ex vivo autopsy data n order to provide a second level of validation. The main hypothesis is that genes within relevant molecular pathways identified in preliminary analyses (lipid transportation, genetic stability, and tau phosphorylation) will predict resilience to the pathologic cascade in dementia. Based on this hypothesis, the primary aims of this application will identify and replicate genetic variants that:1) confer resilience from tau- and amyloid- related cognitive decline; 2) modify relations between vascular risk, cerebrovascular disease, and cognitive decline; and 3) modify the relationship between AD and cerebrovascular pathologies. The complimentary training plan will equip the candidate with the skills necessary to build out an independent research career focused on genetic resilience by emphasizing the following training content areas: 1) autopsy methodology and advanced metrics of pathology; 2) AD biomarkers quantified in cerebrospinal fluid; 3) Neuroimaging of vascular disease; and 4) the clinical characterization of AD and vascular dementia. The mentor team is made up of experts in each of these content areas and will be combined with the interdisciplinary training program in the Vanderbilt Memory and Alzheimer's Center and the cutting edge computational and genomic resources available at Vanderbilt University Medical Center. Together, these practical and intellectual resources will provide the ideal training environment for the candidate. The primary mentor, Dr. Angela Jefferson, has a strong funding history and all the financial resources needed to support the candidate. These extensive resources will allow the candidate to dedicate 100% protected effort as an Assistant Professor to focus on research and career development. This will ensure that Dr. Hohman is fully prepared to compete for independent funding (R01) over the course of the proposed award period.